CN104447728B - Oxazolidinones and the application in medicine thereof - Google Patents

Abstract

The invention relates to a class of oxazolidinone compounds and their application in the preparation of medicines for preventing and treating thromboembolism. In particular, the present invention relates to compounds represented by general formula (I), wherein or stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutical The above acceptable salts or prodrugs, each variable is as defined in the description. The present invention also relates to the stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or Use of salts of prodrugs as medicaments, especially as medicaments for the prophylaxis and treatment of thromboembolic disorders.

Description

Oxazolidinone compounds and their application in medicine

technical field

The invention belongs to the field of medicines, and in particular relates to a novel oxazolidinone compound, a pharmaceutical composition, and its use as a medicine for preparing a factor Xa inhibitor, and in particular to its use as a medicine for preparing factor Xa inhibitors and for treating thrombus Use in embolic disorders.

Background technique

The main practical role of activated factor Xa is the generation of thrombin by limited proteolysis of thrombin. Factor Xa occupies a central position in the final general pathway of blood coagulation, linking intrinsic and extrinsic activation mechanisms. Thrombin is the final serine protease in the pathway to generate a fibrin clot. The generation of thrombin from its precursors is amplified by the formation of the prothrombin complex (factor Xa, factor V, Ca ²⁺ and phospholipids). One factor Xa molecule can generate 138 thrombin molecules (Elodi, a., Varadi, K.: Optimization of conditions for the catalytic effect of the factor IXa–factor VIII complex: Probable role of the complex in the amplification of blood coagulation. Thromb. Res.1979,15,617-629), so inhibiting factor Xa may be more effective than inactivating thrombin in interfering with the coagulation system.

Therefore, there is a need for potent and specific factor Xa inhibitors as potentially valuable therapeutic agents for the treatment of thromboembolic disorders. The present invention relates to novel factor Xa inhibitors; preferably with improved pharmacological properties; more preferably with higher factor Xa inhibitory activity and better selectivity; and/or preferably with the following advantages and improved properties, But not limited to, pharmaceutical properties (such as solubility, permeability, and suitability for sustained-release formulations), dosing requirements (such as lower doses and/or once-daily doses), factors that reduce blood concentrations characterized by peak and trough ( factors that increase active drug concentration (eg, protein binding, volume of distribution), factors that reduce the propensity for clinical drug-drug interactions (eg, inhibition or induction of cytochrome P450 enzymes), factors that reduce adverse side effects Factors of possibility (e.g., pharmacological selectivity other than serine proteases, possible chemical or metabolic reactivity, and limited CNS permeability) and factors that improve manufacturing cost or feasibility (e.g., difficulty of synthesis, proximity of chiral centers number, chemical stability, and ease of handling).

Contents of the invention

The present invention provides a compound, or its pharmaceutical composition, which can effectively treat thromboembolic diseases related to inhibitory factor Xa.

In one aspect, the present invention relates to a compound, which is a compound as shown in formula (I), or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrated compounds, solvates, metabolites, pharmaceutically acceptable salts or prodrugs,

Wherein, R is C _6-10 aryl, C _2-10 heteroaryl, or NHR ¹ ; and

R ¹ is C _6-10 aryl or C _2-10 heteroaryl;

Wherein the C _6-10 aryl or C _2-10 heteroaryl are independently and optionally substituted by one or more substituents selected from F, Cl, Br, I.

In some embodiments,

R is phenyl, five or six membered heteroaryl, NHR ¹ ; and

R ¹ is phenyl, five-membered or six-membered heteroaryl;

The phenyl group, five-membered or six-membered heteroaryl group are independently and optionally substituted by substituents selected from F, Cl, Br and I.

In other embodiments,

R is:

The present invention relates to one of the following compounds or their stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs ,

On the one hand, the present invention also provides a pharmaceutical composition containing the compound described in the present invention, the pharmaceutical composition contains the compound described in the present invention, and its pharmaceutically acceptable carrier, excipient, diluent , adjuvant, vehicle or a combination thereof.

In another aspect, the present invention relates to the use of the compound or the pharmaceutical composition in the preparation, prevention, treatment or treatment of thromboembolic diseases.

In some embodiments, the use of the present invention, wherein the thromboembolic disease is myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, stroke, transient partial Ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.

In some embodiments, the use of the present invention is the use of the compound or the pharmaceutical composition for preparing a medicament for treating disseminated intravascular coagulation (DIC).

In some other embodiments, the use of the present invention is the use of the compound or the pharmaceutical composition for preparing a medicament for inhibiting factor Xa.

Another aspect of the present invention relates to processes for the preparation, isolation and purification of compounds encompassed by formula (I).

The present invention encompasses the use of compounds of the present invention and pharmaceutically acceptable salts thereof for the manufacture of medicinal products for the treatment of thromboembolic diseases in patients, including those described herein. The present invention includes a pharmaceutical composition comprising a compound represented by formula (I) in combination with at least one pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle for effective treatment quantity. The present invention also includes a method for effectively inhibiting the disease of osteoporosis, or for sensitizing it, the method comprising treating the patient with a therapeutically effective amount of the compound represented by formula (I).

Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the present invention are Belong to the scope of the present invention.

In particular, the salts are pharmaceutically acceptable salts. The term "pharmaceutically acceptable" includes that the substance or composition must be chemically or toxicologically appropriate in relation to the other ingredients making up the formulation and the mammal being used for treatment.

The salts of the compounds of the present invention also include the salts of the intermediates of the compounds shown in the formula (I) or the separated enantiomers used in the preparation or purification of the compounds shown in the formula (I), but not necessarily pharmaceutically acceptable Salt.

If the compound of the present invention is basic, the desired salt may be prepared by any suitable method provided in the literature, for example, using inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids and the like. Or use organic acids such as acetic, maleic, succinic, mandelic, fumaric, malonic, pyruvic, malic, 2-hydroxypropionic, citric, oxalic, glycolic, and salicylic ; pyranonic acids, such as glucuronic acid and galacturonic acid; alpha-hydroxy acids, such as citric acid and tartaric acid; amino acids, such as aspartic acid and glutamic acid; aromatic acids, such as benzoic acid and cinnamic acid; Sulfonic acids, such as p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, etc. or combinations thereof.

If the compound of the invention is acidic, the desired salts can be prepared by suitable methods, e.g., using inorganic or organic bases, such as ammonia (primary, secondary, tertiary), alkali metal hydroxides, ammonium , N ⁺ (R ¹⁴ ) ₄ salts and alkaline earth metal hydroxides, etc. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, salts of N ⁺ (R ¹⁴ ) ₄ such as R ¹⁴ is H, C _1-4 alkyl, C _6-10 aryl, C _6-10 aryl C _1-4 alkyl, etc., and cyclic ammonia, such as piperidine, morpholine and piperazine, etc., and from sodium, Calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium give inorganic salts. Also included are suitable, nontoxic ammonium, quaternary ammonium salts and amine cations formed by counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _1-8 sulfonates and Aromatic sulfonates.

Detailed Description of the Invention

Definitions and General Terms

Certain embodiments of the invention are now described in detail, examples of which are illustrated by the accompanying Structural and Chemical Formulas. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions, which are included within the scope of the present invention as defined by the claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this Application shall prevail.

It is further appreciated that certain features of the invention, which, for clarity, have been described in multiple separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications referred to herein are hereby incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise stated. For the purposes of the present invention, the chemical elements correspond to the Periodic Table of the Elements, CAS Edition, and Handbook of Chemistry and Physics, 75th Edition, 1994. In addition, the general principles of organic chemistry can refer to the descriptions in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, Its entire content is incorporated herein by reference.

The term "subject" as used in the present invention refers to an animal. Typically the animal is a mammal. Subjects, for example, also refer to primates (such as humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.

As described in the present invention, the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds. In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced by a particular substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given formula can be substituted by one or more substituents selected from a particular group, then the substituents can be substituted at each position the same or differently.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, a "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes cases where the heterocycle group is substituted with an alkyl group and cases where the heterocycle group is not substituted with an alkyl group .

In various sections of the invention linking substituents are described. When the structure clearly requires a linking group, the Markush variables recited for that group are to be understood as linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable recites "alkyl" or "aryl," it is understood that "alkyl" or "aryl" respectively represents the linking group. An alkylene group or an arylene group.

The term "alkyl" used in the present invention includes a saturated linear or branched monovalent hydrocarbon group of 1-20 carbon atoms, wherein the alkyl group can be independently and optionally substituted by one or more substituents described in the present invention. In some embodiments, the alkyl group contains 1-10 carbon atoms, in other embodiments, the alkyl group contains 1-8 carbon atoms, in other embodiments, the alkyl group contains 1-6 carbon atoms, in other embodiments, the alkyl group contains 1-4 carbon atoms, in other embodiments, the alkyl group contains 1-3 carbon atoms. Further examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), n-propyl (n-Pr, -CH ₂ CH ₂ CH ₃ ), isopropyl (i-Pr, -CH(CH ₃ ) ₂ ), n-butyl (n-Bu, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methylpropyl or isobutyl (i-Bu, -CH ₂ CH(CH ₃ ) ₂ ), 1-methylpropyl or sec-butyl (s-Bu, -CH(CH ₃ )CH ₂ CH ₃ ), tert-butyl (t-Bu , -C(CH ₃ ) ₃ ) and so on.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbocyclic ring systems containing 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic family in which each ring system contains rings of 3-7 atoms and has one or more points of attachment to the rest of the molecule. The term "aryl" is used interchangeably with the term "aromatic ring". Examples of aryl groups may include phenyl, naphthyl and anthracene. The aryl groups may be independently optionally substituted with one or more substituents described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, And at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring composed of 5-7 atoms and has one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl" or "heteroaromatic". The heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, the heteroaryl group of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl , 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2- Pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (such as 2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- Triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5- Triazinyl; also includes, but is by no means limited to, the following bicyclic rings: benzimidazolyl, benzofuryl, benzothienyl, indolyl (eg 2-indolyl), purinyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl), imidazole And[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazole And[1,5-a]pyridyl, etc.

The term "halogen" or "halogen atom" refers to F, Cl, Br or I.

As described in the present invention, substituents A ring system formed by a bond to a ring in the center represents a substituent Substitution can be at any substitutable position on the ring. For example, formula c represents that any position that may be substituted on ring A or ring B can be substituted by R.

Unless otherwise indicated, the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Accordingly, individual stereochemical isomers of the compounds of the present invention or mixtures thereof as enantiomers, diastereomers, or geometric isomers (or conformational isomers) are within the scope of the present invention.

The term "prodrug" used in the present invention means that a compound is transformed into a compound represented by formula (I) in vivo. Such conversion is effected by prodrug hydrolysis in blood or enzymatic conversion in blood or tissue to the parent structure. The prodrug compound of the present invention can be an ester. In the existing invention, the ester can be used as a prodrug with phenyl esters, aliphatic (C _1-24 ) esters, acyloxymethyl esters, and carbonates. , carbamates and amino acid esters. For example, a compound of the present invention that contains a hydroxyl group can be acylated to give a prodrug form of the compound. Other prodrug forms include phosphate esters, eg, phosphorylated parent hydroxyl groups. A complete discussion of prodrugs can be found in the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al, Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al, Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry, 2008, 51, 23 2345.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention. In addition, unless otherwise indicated, the structural formulas of the compounds described herein include enriched isotopes of one or more different atoms.

"Metabolite" refers to a product obtained through metabolism of a specific compound or its salt in vivo. Metabolites of a compound can be identified by techniques known in the art, and their activity can be characterized using assays as described herein. Such products can be obtained by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, degreasing, enzymatic cleavage and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds, including metabolites produced by contacting a compound of the invention with a mammal for a substantial period of time.

Definitions of stereochemistry and usage of conventions in the present invention are generally referred to in the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. , "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomers. All stereoisomeric forms of the compounds of the present invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention part. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center. The prefixes d, l or (+), (-) are used to name the symbol of the plane polarized light rotation of the compound, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their three-dimensional structures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomers, devoid of optical activity.

"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. .

The term "tautomer" or "tautomeric form" means that isomers of structures of different energies can be interconverted through a low energy barrier. For example, proton tautomers (ie, prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Atomic (valency) tautomers include interconversions of rearranged bonding electrons.

The "pharmaceutically acceptable salt" used in the present invention refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66:1-19, 1977. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange methods recorded in books and literature these salts. Other pharmaceutically acceptable salts include adipate, malate, 2-hydroxypropionate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate , borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, transbutene di Glucoheptonate, Glycerophosphate, Gluconate, Hemisulfate, Heptanoate, Hexanoate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lactobionate, Lactic Acid Salt, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate , pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoic acid Salt, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. The present invention also contemplates the quaternary ammonium salts of any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed as counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C _{1 -8} sulfonates and aromatic sulfonates.

A "solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.

The term "protecting group" or "Pg" refers to a substituent that reacts with another functional group, usually to block or protect specific functionality. For example, "amino-protecting group" refers to a substituent attached to the amino group to block or protect the functionality of the amino group in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxy group used to block or protect the functionality of the hydroxy group, suitable protecting groups include acetyl and silyl groups. "Carboxyl protecting group" refers to the substituent of carboxyl to block or protect the functionality of carboxyl. General carboxyl protecting groups include -CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2-(trimethylsilane base) ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrobenzenesulfonyl)ethyl, 2-(diphenyl phosphino)ethyl, nitroethyl, etc. A general description of protecting groups can be found in: T W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and PJ Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

In addition, the compounds disclosed in the present invention, including their salts, can also be obtained in the form of their hydrates or in the form of solvents (such as ethanol, DMSO, etc.) containing them for their crystallization. The compounds disclosed herein may inherently or by design form solvates with pharmaceutically acceptable solvents, including water; thus, it is intended that the present invention embrace both solvated and unsolvated forms.

Any structural formulas given herein are also intended to represent non-isotopically enriched as well as isotopically enriched forms of these compounds. Isotopically enriched compounds have structures depicted by the general formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Exemplary isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O , ¹⁸ O, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I.

In another aspect, the compounds of the present invention include isotopically enriched compounds as defined in the present invention, for example, those compounds in which radioactive isotopes such as ³ H, ¹⁴ C and ¹⁸ F are present, or in which non-radioactive isotopes such as ² H and ¹³ C. Such isotopically enriched compounds can be used in metabolic studies (using ¹⁴ C), reaction kinetics studies (using e.g. ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or including pharmaceutical or Single-photon emission computed tomography (SPECT) for the determination of substrate tissue distribution may be used in radiation therapy of patients. ¹⁸ F-enriched compounds are particularly ideal for PET or SPECT studies. The isotope-enriched compound represented by formula (I) can be prepared by using a suitable isotope-labeled reagent to replace the previously used unlabeled reagent by conventional techniques familiar to those skilled in the art or as described in the examples and preparation processes of the present invention.

^In addition, substitution with heavier isotopes, particularly deuterium (ie,2H or D), may afford certain therapeutic advantages resulting from greater metabolic stability. For example, due to increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium in the present invention is considered as a substituent of the compound of formula (I). An isotopic enrichment factor can be used to define the concentration of such heavier isotopes, especially deuterium. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has, for each designated deuterium atom, at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), At least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation) Deuterium incorporation), an isotopic enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the present invention include those wherein the solvent of crystallization may be isotopically substituted eg _D2O , acetone _- d6, _DMSO -d6.

Compound of the present invention and pharmaceutical composition, preparation and use

According to another aspect, the characteristics of the pharmaceutical composition of the present invention include the compound shown in formula (I), the compound listed in the present invention, or the compound of embodiment 1-3, and pharmaceutically acceptable carrier, adjuvant , or excipients. The amount of compound in the composition of the invention is effective to treat or alleviate thromboembolic disease in a patient or act as a factor Xa inhibitor.

The compounds of the present invention exist in free form, or suitably, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other compounds that can be administered directly or indirectly according to the needs of patients. Adducts or derivatives, compounds described in other aspects of the present invention, their metabolites or their residues.

As described herein, the pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used in the present invention, includes any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form. As described in: In Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, synthesis of the literature herein, shows that different carriers can be used in the formulation of pharmaceutically acceptable compositions and their known methods of preparation. Except to the extent that any conventional carrier media is incompatible with the compounds of the present invention, such as any adverse biological effects produced or interactions in a deleterious manner with any other components of the pharmaceutically acceptable composition, they The purposes of the present invention are also considered scope.

Substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, sorbic acid, Potassium phosphate, partial glyceride mixture of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon, magnesium trisilicate, polyethylene Pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-blocking polymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethyl sodium cellulose, ethyl cellulose, and cellulose acetate; gum powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, Olive, corn, and soybean oils; glycols, such as propylene glycol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; seaweed acid; pyrogen-free water; isotonic salts; Ringer's solution; ethanol, phosphate buffered solution, and other nontoxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, Coatings, sweeteners, flavors and fragrances, preservatives and antioxidants.

The compounds of the present invention may be administered in the form of oral dosage forms such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups , and emulsifiers. They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all dosage forms used are well known to those skilled in the art of pharmacy. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen mode of administration and standard pharmaceutical practice.

The dosing regimen of the compounds of the present invention will vary with known various factors, such as the pharmacokinetic profile of the particular agent and its mode and route of administration; the race, age, sex, health, medical condition and weight of the recipient; Nature and extent of symptoms; type of concurrent therapy; frequency of therapy; route of administration, patient's renal and hepatic function, and desired effect. A physician or veterinarian can make the determination and prescribe an effective amount of drug to prevent, counteract or arrest the development of thromboembolic disease.

As a general guideline, the daily oral dose of each active ingredient used in order to achieve the indicated effect is in the range of about 0.001 to 1000 mg/kg body weight, preferably, between about 0.01 to 100 mg/kg body weight . And, most preferably, between about 1.0 and 20 mg/kg body weight/day. For intravenous administration, the most preferred dosage range is about 1 to about 10 mg/kg body weight/minute during a conventional rate infusion. The compounds of the present invention may be administered once daily, or may be administered in two, three or four divided times daily.

The compounds of the invention may be administered in intranasal form via topical use of suitable intranasal vehicles, or by the transdermal route through the use of transdermal patches. When administered in the form of a transdermal delivery system, the dosage administration will be continuous rather than intermittent throughout the dosage period.

Typically, the compound is administered in admixture with a suitable pharmaceutical diluent, excipient, or carrier (herein referred to as a pharmaceutical carrier) selected according to the form of administration and conventional pharmaceutical practice, and the administration mode may be an oral tablet, Capsules, elixirs, syrups and more.

For example, for oral administration in tablet or capsule form, the active pharmaceutical ingredient can be combined with an oral, nontoxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, , magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.; for oral administration in liquid form, the oral pharmaceutical composition can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier Combined, such as ethanol, glycerin, water and so on. Also, when desired or necessary, suitable binders, lubricants, disintegrating agents, and colorants may also be added to the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene Glycols, waxes and more. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the invention can also be administered in the form of liposomal delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of the invention are also coupled to soluble polymers which serve as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamine-phenol, polyhydroxyethylaspartamidephenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. acid. Moreover, the compounds of the present invention can be coupled with a class of biodegradable polymers for controlled drug release, for example, polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyεcaprolactone esters, polyhydroxybutyrates, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic blocked copolymers of hydrogels. Dosage forms suitable for administration (pharmaceutical compositions) may contain from about 1 mg to about 100 mg of the active ingredient per unit dose. In these pharmaceutical compositions, the active ingredient will generally comprise from about 0.5% to about 95% by weight of the total composition.

Gelatin capsules may contain the active ingredient along with powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Compressed tablets can be made using similar diluents. Tablets and capsules can be manufactured as sustained release products to provide continuous release of a drug over a period of time. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and seal the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain colorings and flavorings to increase patient acceptance.

In general, water, a suitable oil, saline, hydrated dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidants are suitable stabilizers, such as sodium bisulfite, sodium sulfite, or vitamin C, either alone or in combination, as well as citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as germine, methyl- or propyl-paraben, and chlorobutanol.

Where the compounds of the present invention are combined with other anticoagulants, for example, a daily dose may be about 0.1 to 100 mg of a compound of formula (I) and about 1 to 7.5 mg of a second anticoagulant per kg of patient body weight . For a tablet dosage form, the compound of the invention may generally be from about 5 to 10 mg per dosage unit, and the amount of the second anticoagulant agent is from about 1 to 5 mg per dosage unit. Among them, other anticoagulant agents specifically include, but are not limited to, apixaban, rivaroxaban, edoxaban, betrixaban, dabigatran, bemiparin, enoxaparin sodium, tinza Heparin Sodium, Danaparin Sodium, Pentosan Sodium, Nadroparin Calcium, Adeparin Sodium, Parparin Sodium, etc.

According to general guidelines, the compound of the present invention is administered in combination with an antiplatelet agent, and the general daily dose may be about 0.01 to 25 mg of the compound of formula (I) and about 50 to 150 mg of the antiplatelet agent per kilogram of patient body weight, preferably About 0.1 to 1 mg of a compound of formula (I) and about 1 to 3 mg of an antiplatelet agent. When the compound of formula (I) is administered in combination with a thrombolytic agent, the general daily dose can be about 0.1 to 1 mg of the compound of formula (I) per kilogram of patient body weight, and in the presence of the thrombolytic agent, the combination with the thrombolytic When the thrombolytic agent is administered together with a compound of formula (I), the dosage of the thrombolytic agent can be reduced by about 70-80% compared to the usual dosage when the agent is administered alone.

When two or more aforementioned second therapeutic agents are administered together with the compound of formula (I), in general, considering the additive or synergistic effects of the therapeutic agents during combined administration, the typical daily dose and typical dosage form The amount of each component may be reduced relative to the usual dosage when administered alone.

In particular, when presented as a single dosage unit, there exists the possibility of chemical reactions between the active ingredients in combination. For this reason, when a compound of formula (I) and a second therapeutic agent are combined in a single dosage unit, they are formulated in such a way that physical contact between the active ingredients is minimized (i.e., reduced), although The active ingredients are combined in a single dosage unit. For example, an active ingredient may be enteric coated. By coating an active ingredient with an enteric coating, it is possible not only to minimize contact between the combined active ingredients, but also to control the release of one of these ingredients in the gastrointestinal tract so that one of the ingredients does not Released not in the stomach but in the small intestine. One of the active ingredients can also be coated with materials that affect its sustained release in the gastrointestinal tract and can also be used to reduce physical contact between the combined active ingredients. Further, the sustained release component can additionally be coated with an enteric coating in order to Release of this ingredient occurs only in the intestinal tract. Still another approach involves the formulation of combination products in which one component is coated with a sustained and/or enteric release polymer and the other component is also coated with a polymer such as a low viscosity grade of hydroxyl Propyl methylcellulose (HPMC) or other suitable materials known in the art are coated to achieve the purpose of further separating the active ingredients. The polymer coating creates an additional barrier to reaction with other components.

These and other methods of minimizing contact between the components of the combination products of the invention will be apparent to those skilled in the art once apprised of the present disclosure, whether administered in a single dosage form or in separate forms, But at the same time or in the same way.

The compounds involved in the present invention or their pharmaceutically acceptable salts or their hydrates can be effectively used for the prevention, treatment, treatment or alleviation of thromboembolic diseases in patients, especially for the effective treatment of myocardial infarction, angina pectoris, reocclusion and angioplasty or aortic Restenosis after coronary bypass, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism, or deep vein thrombosis.

The general synthesis method of this compound

Generally, the compounds of the present invention can be prepared by the methods described in the present invention, and unless otherwise specified, the definitions of the substituents are as shown in formula (I). The following reaction schemes and examples serve to further illustrate the present invention.

Those skilled in the art will recognize that the chemical reactions described herein can be used to suitably prepare many other compounds of the invention and that other methods for preparing the compounds of the invention are considered to be within the scope of the invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described in the present invention, or by incorporating Reaction conditions with some routine modifications. In addition, reactions disclosed herein or known reaction conditions are also recognized to be applicable to the preparation of other compounds of this invention.

In the examples described below, unless indicated otherwise, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Linkchem Pharmaceuticals, Aldrich Chemical Company, Inc., Arco Chemical Company and Alfa Chemical Company, and were used without further purification unless otherwise indicated. Common reagents were purchased from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Haiyang Chemical Factory.

Anhydrous tetrahydrofuran was obtained by reflux drying over sodium metal. Anhydrous dichloromethane and chloroform were obtained by refluxing and drying over calcium hydride. Ethyl acetate, N,N-dimethylacetamide and petroleum ether were dried over anhydrous sodium sulfate before use.

The following reactions were generally carried out under a positive pressure of nitrogen or argon or over anhydrous solvents with a dry tube (unless otherwise indicated), the reaction vials were fitted with suitable rubber stoppers, and the substrate was introduced by syringe. Glassware is dried.

The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory. The nuclear magnetic resonance spectrum uses CDC1 ₃ or DMSO-d ₆ as the solvent (reported in ppm), and uses TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiplets appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broadened) peak), dd (doublet of doublets, quartet), dt (doublet of triplets, double triplet). Coupling constants are expressed in Hertz (Hz).

Low-resolution mass spectrometry (MS) data was determined by an Agilent6320 series LC-MS spectrometer equipped with a G1312A binary pump and a G1316A TCC (column temperature maintained at 30°C), and a G1329A autosampler and G1315B DAD detector were used for analysis , the ESI source was applied to the LC-MS spectrometer.

Low-resolution mass spectrometry (MS) data is measured by the spectrometer of Agilent6120 series LC-MS equipped with G1311A quaternary pump and G1316A TCC (column temperature is maintained at 30 ° C), G1329A automatic sampler and G1315D DAD detector are used for analysis, ESI sources are applied to LC-MS spectrometers.

The above two spectrometers are equipped with Agilent Zorbax SB-C18 column, the specification is 2.1×30mm, 5μm. Injection volume was determined by sample concentration; flow rate was 0.6 mL/min; HPLC peaks were recorded and read by UV-Vis wavelengths at 210 nm and 254 nm. The mobile phases were 0.1% formic acid in acetonitrile (phase A) and 0.1% formic acid in ultrapure water (phase B). Gradient elution conditions are shown in Table 1:

Table 1

time (min) A ( _CH3CN , 0.1% HCOOH) B( _H2O , 0.1%HCOOH) 0-3 5-100 95-0 3-6 100 0 6-6.1 100-5 0-95 6.1-8 5 95

Compound purification was evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), wherein UV detection was at 210nm and 254nm, Zorbax SB-C18 column, specification was 2.1×30mm, 4 μm, 10 minutes, flow rate was 0.6mL/min , 5-95% (0.1% formic acid in acetonitrile solution) of (0.1% formic acid in water), the column temperature was kept at 40°C.

The following abbreviations are used throughout this disclosure:

CDC1 ₃ deuterated chloroform

g grams

mg mg

mole mole

mmol millimole

hours

mL milliliter

ESI electrospray ionization

m/z mass-to-charge ratio

PT plasma prothrombin time

APTT activated partial thromboplastin time

FXa Factor Xa

HATU 2-(7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HBTU Benzotriazole N,N,N',N'-tetramethyluronium hexafluorophosphate

Synthetic scheme

Synthesis scheme 1:

The target product 10a can be prepared by the method described in Synthesis Scheme 1, wherein R has the meaning as described in the present invention.

Raw material 1a and raw material 2a remove a portion of water under the action of a dehydrating agent (such as trifluoroacetic anhydride) to generate intermediate 3a; intermediate 3a and raw material 4a are heated in a solvent under the action of a base (such as triethylamine) Curtis rearrangement occurs to generate intermediate 5a; intermediate 5a undergoes amidation reaction with raw material 6a under the action of alkali to generate intermediate 7a; intermediate 7a undergoes saponification reaction under alkaline conditions to generate intermediate 8a; intermediate 8a and raw material 9a is condensed under the action of a condensing agent (such as HATU and HBTU) to generate the target product 10a.

Synthesis Scheme 2:

Intermediate 7b can be prepared by the method described in Synthesis Scheme 2, wherein R ¹ has the meaning as described in the present invention.

The raw material 11a and the raw material 12a are heated in a solvent to generate an intermediate 13a; the intermediate 13a and the intermediate 5 are reacted with a base to generate an intermediate 7b.

Synthetic Scheme 3

The target product 18a can be prepared by the method described in Synthesis Scheme 3, wherein R ¹ has the meaning as described in the present invention.

The raw material 14a and the raw material 12a are ring-closed under heating conditions to generate intermediate 15a; intermediate 15a and 13a generate intermediate 16a under the action of alkali; intermediate 16a is hydrolyzed under acid (such as concentrated HCl) to generate intermediate 17a ; The intermediate 17a is condensed with the raw material 9a under the action of a condensing agent (such as HATU and HBTU) to generate the target product 18a.

detailed description

The following examples can further describe the present invention, however, these examples should not be construed as limiting the scope of the present invention.

Example 1: 3-(5-chlorothiophene-2-formyl)-2-oxo-N-(4-(2-oxopiperidin-1-yl)phenyl)oxazolidine-5-methan Amide

Step 1: 4-(Benzyloxy)-2-hydroxy-4-oxobutanoic acid

2,2,2-Trifluoroacetic anhydride (100 g, 476 mmol) was added to 2-hydroxysuccinic acid (26.6 g, 198 mmol) at 0°C, and stirring was continued at 0°C for 3 hours. At 0°C, volatiles were distilled off under reduced pressure. The residue was dissolved in benzyl alcohol (300 mL) and stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (200 mL), extracted with 10% sodium carbonate solution (200 mL×3), the aqueous phases were combined, acidified to pH 7 with hydrochloric acid, and unreacted benzyl alcohol was removed by extraction with ethyl acetate (300 mL) . The aqueous phase was further acidified to pH 2 with hydrochloric acid, extracted with ethyl acetate (150 mL×3), the combined organic phases were washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a white solid ( 43.0 g, 96.7%).

MS(ESI,neg.ion)m/z:223.9(M-1)

Step 2: Benzyl 2-oxooxazolidine-5-carboxylate

Add 4-(benzyloxy)-2-hydroxy-4-oxobutanoic acid (43.0 g, 192 mmol), diphenylphosphoryl azide (63.0 g, 229 mmol), triethylamine (23.0 g, 227mmol) and dry toluene (500mL), heated to 110°C and stirred for 4 hours. The solvent was evaporated under reduced pressure, water (250 mL) was added, and extracted with ethyl acetate (100 mL×4). The organic phases were combined, washed with saturated sodium bicarbonate (100 mL×3), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a white solid (14.0 g, 33.0%).

MS(ESI,pos.ion)m/z:222.1(M+1)

Step 3: Benzyl 3-(5-chlorothiophene-2-formyl)-2-oxooxazolidine-5-carboxylate

Benzyl 2-oxooxazolidine-5-carboxylate (1.11 g, 5.02 mmol), triethylamine (2.0 mL, 14.4 mmol) and dry toluene (20 mL) were added sequentially to a round bottom flask. A solution of 5-chlorothiophene-2-formyl (905 mg, 5.00 mmol) in dry toluene (20 mL) was slowly added thereto at 0°C. Raise to room temperature and stir for 12 hours. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/2) to obtain a light gray solid (1.5 g, 81.7%).

MS(ESI,pos.ion)m/z:366.1(M+1).

Step 4: 3-(5-Chlorothiophene-2-formyl)-2-oxooxazolidine-5-carboxylic acid

To a solution of benzyl 3-(5-chlorothiophene-2-formyl)-2-oxooxazolidine-5-carboxylate (1.0 g, 2.73 mmol) in THF (20 mL) was added potassium carbonate at 0 °C (1.6g, 11.6mmol) in water (20mL) was stirred at 0°C for 2 hours. Extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with saturated brine (40 mL), and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/2) to obtain a light gray solid (100 mg, 13.3%).

MS (ESI, neg.ion) m/z: 274.0 (M-1).

Step 5: 3-(5-Chlorothiophene-2-formyl)-2-oxo-N-(4-(2-oxopiperidin-1-yl)phenyl)oxazolidine-5-carboxamide

To a solution of 3-(5-chlorothiophene-2-formyl)-2-oxooxazolidine-5-carboxylic acid (100 mg, 0.363 mmol) in N,N-dimethylformamide (3 mL) was added triethyl Amine (138 μL, 0.993 mmol) and HBTU (204.8 mg, 0.540 mmol), after stirring at room temperature for 10 minutes, 1-(4-aminophenyl)piperidin-2-one (82 mg, 0.431 mmol) was added. Stir at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/methanol (v/v)=10/1) to obtain a pale yellow solid (50 mg, 30.8%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.62 (1H, s), 7.83 (1H, d, J = 4.2), 7.51 (2H, d, J = 8.7), 7.18 (2H, d, J = 8.7) ,6.96(1H,d,J=4.2),5.12(1H,dd,J ₁ ＝9.4,J ₂ ＝6.4),4.30-4.45(2H,m),3.60-3.64(2H,m),2.54-2.56 (2H,m),1.94-1.96(4H,m);

MS(ESI,pos.ion)m/z:448.00(M+1).

Example 2: N ³ -(5-chloropyridin-2-yl)-2-oxo-N ⁵ -(4-(2-oxopiperidin-1-yl)phenyl)oxazolidine-3, 5-dicarboxamide

Step 1: 5-Chloro-2-isocyanatopyridine

To a solution of triphosgene (2.4 g, 8.09 mmol) in toluene (30 mL) was added 5-chloropyridin-2-amine (2.1 g, 16.3 mmol). Heat to 110°C and stir for 7 hours. The solvent was evaporated under reduced pressure, and the crude product was directly used in the next step without purification.

Step 2: Benzyl 3-((5-chloropyridin-2-yl)carbamoyl)-2-oxooxazolidine-5-carboxylate

To a solution of benzyl 2-oxazolidine-5-carboxylate (1.8 g, 8.14 mmol) in toluene (20 mL) was added 5-chloro-2-isocyanatopyridine (1.3 g, 8.41 mmol) and triethylamine ( 1 mL). Heat to 110°C and stir for 7 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain a yellow solid (300 mg, 9.8%).

MS(ESI,pos.ion)m/z:376.0(M+1).

Step 3: 3-((5-Chloropyridin-2-yl)carbamoyl)-2-oxooxazolidine-5-carboxylic acid

Add 3-((5-chloropyridin-2-yl)carbamoyl)-2-oxooxazolidine-5-carboxylic acid benzyl ester (400mg, 1.06mmol) in tetrahydrofuran (15mL) at 0°C A solution of potassium carbonate (400 mg, 2.89 mmol) in water (10 mL) was added. Stirring was continued at 0°C until the reaction was complete as monitored by TLC. Add hydrochloric acid to acidify to pH 2, extract with ethyl acetate (20 mL×3), combine organic phases, wash with saturated brine (30 mL), and dry over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/methanol (v/v)=10/1) to obtain a yellow solid (100 mg, 32.9%).

MS (ESI, neg.ion) m/z: 283.90 (M-1).

Step 4: N ³ -(5-chloropyridin-2-yl)-2-oxo-N ⁵ -(4-(2-oxopiperidin-1-yl)phenyl)oxazolidine-3,5 - Diformamide

To 3-((5-chloropyridin-2-yl)carbamoyl)-2-oxooxazolidine-5-carboxylic acid (100mg, 0.350mmol) in N,N-dimethylformamide (3mL) solution Add triethylamine (138μL, 0.993mmol) and HBTU (204.8mg, 0.540mmol), after stirring at room temperature for 10 minutes, add 1-(4-aminophenyl)piperidin-2-one (82mg, 0.431mmol) . Stir at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate/methanol (v/v)=10/1) to obtain a pale yellow solid (30 mg, 18.7%).

¹ H NMR (400MHz, CDCl ₃ ) δ8.21(d, J=2.1Hz, 1H), 7.99(d, J=9.0Hz, 1H), 7.71–7.62(m, 2H), 7.58(d, J= 8.8Hz, 2H), 7.17(d, J=8.8Hz, 2H), 5.14(dd, J=9.6, 6.2Hz, 1H), 4.41–4.23(m, 2H), 4.04(d, J=6.7Hz, 1H),3.66–3.53(m,2H),3.32-3.26(m,1H),2.51(d,J＝6.1Hz,2H),1.98–1.84(m,4H);

MS(ESI,pos.ion)m/z:458.20(M+1)

Example 3: N ³ -(5-chloropyridin-2-yl)-2-oxo-N ⁴ -(4-(2-oxopiperidin-1-yl)phenyl)oxazolidine-3, 4-Formamide

Step 1: Methyl 2-oxooxazolidine-4-carboxylate

To a solution of DL-serine methyl ester hydrochloride (10.40 g, 67 mmol) in tetrahydrofuran (250 mL) was slowly added triphosgene (20.00 g, 67 mmol). Heat to 80°C and stir for 12 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=1/1) to obtain a white solid (8.20 g, 84.0%).

MS(ESI,pos.ion)m/z:146.1(M+1)

Step 2: 5-Chloro-2-isocyanatopyridine

To a solution of triphosgene (890.0 mg, 3 mmol) in toluene (20 mL) was added 5-chloropyridine-2-ammonia (770.0 mg, 6 mmol). Heat to 120°C and stir for 7 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was directly used in the next step without purification.

Step 3: Methyl 3-((5-chloropyridin-2-yl)carbamoyl)-2-oxooxazolidine-4-carboxylate

To a toluene solution of 5-chloro-2-isocyanatopyridine (610.0mg, 4mmol), add 2-oxooxazolidine-4-carboxylic acid methyl ester (580.0mg, 4mmol) and triethylamine (3.0mL, 21mmol) successively ). Heat to 70°C and stir for 8 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/ethyl acetate (v/v)=2/1) to obtain a white solid (500.0 mg, 42.0%).

MS(ESI,pos.ion)m/z:300.0(M+1)

Step 4: 3-((5-Chloropyridin-2-yl)carbamoyl)-2-oxooxazolidine-4-carboxylic acid

3-((5-Chloropyridin-2-yl)carbamoyl)-2-oxooxazolidine-4-carboxylic acid methyl ester (150.0mg, 0.5mmol) in methanol (4mL) at -10°C Concentrated hydrochloric acid (2 mL) was added dropwise to the solution. Heat to 90°C and stir for 9 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (dichloromethane/methanol (v/v)=20/1) to obtain a white solid (89.0 mg, 62.0%).

MS(ESI,neg.ion)m/z:284.0(M-1)

Step 5: N ³ -(5-chloropyridin-2-yl)-2-oxo-N ⁴ -(4-(2-oxopiperidin-1-yl)phenyl)oxazolidine-3,4 -Formamide

To 3-((5-chloropyridin-2-yl)carbamoyl)-2-oxooxazolidine-4-carboxylic acid (89.0 mg, 0.31 mmol) in N,N-dimethylformamide (3 mL) Add benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate (176.4mg, 0.465mmol) and triethylamine (138μL, 1mmol) successively, and stir at room temperature for 10 minutes After that, 1-(4-aminophenyl)piperidin-2-one (70.0 mg, 0.372 mmol) was added, and stirring was continued at room temperature for 4 hours. The solvent was evaporated under reduced pressure, and the crude product was purified by column chromatography (ethyl acetate) to obtain a white solid (10.0 mg, 7.0 mg).

MS(ESI,pos.ion)m/z:458.1(M+1);

¹ H NMR (400MHz, CDCl ₃ ) δ10.43 (1H, s), 9.43 (1H, s) 8.26 (1H, s), 8.00 (1H, d, J = 8.9), 7.65 (2H, dd, J ₁ ＝8.7,J2＝2.1Hz),7.34(2H,d,J＝8.4),7.10(2H,d,J＝ _8.2 ),5.70–5.79(1H,m),4.90–5.07(2H,m), 3.57–3.60(2H,m), 2.30–2.34(2H,m), 2.00–2.05(4H,m).

Biological activity test

Human FXa enzyme inhibition assay

The enzymatic activity of human coagulation factor Xa (FXa) is determined by conversion of a chromogenic substrate specific for FXa. For this, Factor Xa cleaves p-nitroaniline from the chromogenic substrate. The assay was performed on a microtiter plate as described below.

Dissolve the test substance in 10% dimethyl sulfoxide at different concentrations, mix 5 μL of the compound with 10 μL of human FXa (10 nM dissolved in 50 mM Tris, 150 mM NaCl, pH=8.3), and incubate for 15 min in a constant temperature incubator at 25 ° C. After incubation, 5 μL of FXa chromogenic substrate (800 μM, sigma) was added, and the absorbance value was measured kinetically at 25° C. at 405 nm. The test mixtures containing the test substances are compared with the control mixtures without the test substances and the _IC50 values are calculated from these data.

In vitro anticoagulation test

Compound prolongs clotting time in rabbit plasma

1. Preparation of compounds at various concentrations

Take 4 μL of the working solution (100 mM) of each compound and dilute it with dimethyl sulfoxide solution to form working solutions of various concentrations.

2. Preparation of Plasma Samples

Take several rabbits, inject 3% pentobarbital solution (30mg/kg) into the ear vein for anesthesia, use a vacuum blood collection tube containing 0.2mL of 3.8% sodium citrate to collect blood from the abdominal aorta to 2mL, collect multiple tubes, and turn them upside down Mix several times, let stand for 10 minutes, centrifuge at 3000rpm for 10 minutes, absorb the plasma from each tube, mix all the plasma into the same centrifuge tube, aliquot 1.6mL in each tube, and quickly store in a -80°C refrigerator for later use.

3. Adding samples and measuring coagulation time PT and APTT

Prepare 1.5mL EP tubes, add 180 μL plasma samples to each tube; add 4 μL of corresponding concentration of drugs to each tube of blood samples, add 4 μL dimethyl sulfoxide solution to the control group, shake and mix, and incubate at 37 °C for 5 minutes; use Sysmex CA1500 The PT and APTT were measured by an automatic coagulation analyzer; the dose-effect curve was drawn, and the curve was fitted to calculate the concentration of the test compound (CT ₂ ) that doubled the coagulation time.

Inhibitory Effect of Compounds on Human FXa Activity and Anticoagulant Effect in Vitro

A: 1.00nM-100.00nM; B: 100.01nM-1.00μM; C: 1.01μM-10.00μM; D: 10.01μM-50.00μM

Conclusion: This series of compounds has good inhibitory activity of blood coagulation factor Xa, and also has the effect of prolonging blood coagulation time.

Solubility testing of compounds

Add water (10 mL) into a 15 mL conical tube, add the sample while shaking until the sample stops dissolving, shake in a constant temperature water bath at 37°C for 24 hours, and shake at a speed of 40 rpm. After shaking, filter the sample through a water-based microporous membrane (0.45 μm, Φ13 mm), discard the initial filtrate, and accurately pipette the subsequent filtrate (500 μL), add diluent acetonitrile-water (500 μL, v/v=60/ 40), the two are mixed to obtain the test solution.

Take the test solution (40 μL), use HPLC to detect, and calculate the sample concentration by the external standard one-point method:

serial number Compound solubility (mg/mL) Example 1 0.35 Example 2 0.78 Example 3 0.66

Conclusion: This series of compounds has good solubility.

In the description of this specification, descriptions referring to the terms "one embodiment", "some embodiments", "example", "specific examples", or "some examples" mean that specific features described in connection with the embodiment or example , structure, material or characteristic is included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the described specific features, structures, materials or characteristics may be combined in any suitable manner in any one or more embodiments or examples. In addition, those skilled in the art can combine and combine different embodiments or examples and features of different embodiments or examples described in this specification without conflicting with each other.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and those skilled in the art can make the above-mentioned The embodiments are subject to changes, modifications, substitutions and variations.

Claims (8)

1. A compound, which is a compound as shown in formula (I), or a pharmaceutically acceptable salt of a compound of formula (I), in, R is: 2. The compound according to claim 1, which is one of the following structures, or a pharmaceutically acceptable salt thereof, 3. A pharmaceutical composition, comprising the compound according to any one of claims 1-2, and a pharmaceutically acceptable adjuvant thereof. 4. The pharmaceutical composition according to claim 3, wherein the pharmaceutically acceptable adjuvant is an excipient, a diluent or any combination thereof. 5. Use of the compound according to any one of claims 1-2 or the pharmaceutical composition according to claim 3 in the preparation of medicines for preventing, treating or alleviating thromboembolic diseases in patients. 6. Use according to claim 5, wherein the thromboembolic disease is myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemic attack , peripheral arterial occlusive disease, or deep vein thrombosis. 7. Use of the compound according to any one of claims 1-2 or the pharmaceutical composition according to claim 3 in the preparation of a medicament for the treatment of disseminated intravascular coagulation (DIC). 8. Use of the compound according to any one of claims 1-2 or the pharmaceutical composition according to claim 3 in the preparation of a medicament for inhibiting factor Xa.